The invention relates to dithiocarboxylic esters and processes for the preparation thereof.
Living polymerization is a method by which polymers having a narrow molecular weight distribution may be obtained. Block copolymers may also be synthesized using the method. Block copolymers may display improved mechanical and/or chemical properties over corresponding random copolymers. Commercial processes for the production of block copolymers typically employ anionic initiators in living polymerization processes. Polymerization processes using free radical initiators have many attractive characteristics and have attained commercial importance. However, these do not include processes with characteristics of living polymerization.
One promising method for free radical polymerization with living characteristics is reversible addition-fragmentation chain transfer (RAFT) polymerization (Moad, 1998). Use of thiocarbonylthio (dithiocarboxylic ester) compounds of structure 
chain transfer agents for RAFT polymerizations is described in International Application Number PCT/US97/12540, published as WO 98/01478 on Jan. 15, 1998. Free radical processes employing these chain transfer agents resulted in polymers having low polydispersity in bulk, emulsion and solution polymerizations. Block copolymers were also successfully prepared.
However, known methods for synthesis of the chain transfer agents are unsatisfactory for various reasons. Literature methods for preparation of dithiocarboxylic esters include: alkylation of ArCS2M (Mxe2x95x90Na or K) or ArCS2MgX with an appropriate alkyl or aryl halide, thiation of S-substituted thioesters using Lawesson""s reagent, transesterifications of dithioesters with thiols, and reaction of bis(thiocarbonyl)disulfides with azo compounds. Disadvantages of these methods include safety, cost and sensitivity concerns regarding the use of Grignard reagents, inability to utilize desirable probe functionalities because of incompatibility with reagents, lack of suitable thiol, thioacid and/or disulfide precursors and, ultimately, low yield from the reactions. It is therefore an object of the present invention to provide a process for the synthesis of dithiocarboxylic esters that eliminates the use of Grignard reagents, allows for synthesis of functional dithiocarboxylic esters, requires inexpensive and readily available starting materials, and provides high yields.
It has been unexpectedly discovered that the processes of the present invention provide an improved method for the synthesis of dithiocarboxylic esters which meets these requirements. In addition, the process operates under mild conditions, and provides for facile isolation of products.
In one aspect, a process according to the present invention for the preparation of a dithiocarboxylic ester of structure I 
comprises reacting a carboxylic acid compound of formula R1(COOH)m, a compound of formula R2AH and phosphorus pentasulfide, wherein R1 is a m-valent radical selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; R2 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, and substituted alkylaryl; A is S or O; and m is an integer from 1-6.
In another aspect, a process according to the present invention comprises:
(a) reacting a compound of formula R3(COAH)m and a compound of structure II 
in the presence of a clay catalyst; and
(b) treating products of the reaction with a thiating agent to produce a compound of structure III, a compound of structure IV, or a combination of compounds of structure III and structure IV; 
wherein R3 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; R4 is a n-valent radical selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl , substituted heteroaryl; R5 is H or lower alkyl; and A is S or O.
In the context of the present invention, alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. Lower alkyl refers to alkyl groups of from 1 to 4 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-and t-butyl. Preferred alkyl groups are those of C20 or below. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, and norbomyl
Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, and cyclohexyloxy. Lower alkoxy refers to groups containing one to four carbons.
Acyl refers to groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, and benzyloxycarbonyl. Lower-acyl refers to groups containing one to four carbons.
Aryl and heteroaryl mean a 5- or 6-membered aromatic or heteroaromatic ring containing 0-3 heteroatoms selected from nitrogen, oxygen or sulfur; a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from Nitrogen, oxygen or sulfur; or a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from Nitrogen, oxygen or sulfur. Each of these rings is optionally substituted with 1-3 lower alkyl, substituted alkyl, substituted alkynyl, carbonyl, nitro, halogen, haloalkyl, hydroxy, alkoxy, OCH(COOH)2, cyano, primary amino, secondary amino, acylamino, phenyl, benzyl, phenoxy, benzyloxy, heteroaryl, or heteroaryloxy; each of said phenyl, benzyl, phenoxy, benzyloxy, heteroaryl, and heteroaryloxy is optionally substituted with 1-3 substitutents selected from lower alkyl, alkenyl, alkynyl, halogen, hydroxy, haloalkyl, alkoxy, cyano, phenyl, benzyl, benzyloxy, carboxamido, heteroaryl, heteroaryloxy, nitro or xe2x80x94NRR (wherein R is independently H, lower alkyl or cycloalkyl, and xe2x80x94RR may be fused to form a cyclic ring with nitrogen). The aromatic 6- to 14-membered carbocyclic rings include, for example, benzene, naphthalene, indane, tetralin, and fluorene; and the 5- to 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
Alkylaryl means an alkyl residue attached to an aryl ring. Examples are benzyl and phenethyl. Heteroarylalkyl means an alkyl residue attached to a heteroaryl ring. Examples include pyridinylmethyl and pyrimidinylethyl.
Heterocycle means a cycloalkyl or aryl residue in which one to two of the carbons is replaced by a heteroatom such as oxygen, nitrogen or sulfur. Examples of heterocycles that fall within the scope of the invention include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, and tetrahydrofuran.
Substituted alkyl, aryl, cycloalkyl, or heterocyclyl refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in each residue are replaced with halogen, haloalkyl, hydroxy, lower alkoxy, carboxy, carboalkoxy, carboxamido, cyano, carbonyl, nitro, primary amino, secondary amino, alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, heteroaryloxy, or substituted phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or heteroaryloxy.
In yet another aspect, the present invention relates to dithiocarboxylic esters having the following structures: 
The present invention is more easily understood when reference is made to general Schemes A and B for the preparation of dithiocarboxylic esters. 
In one embodiment, a process according to the present invention comprises reacting a carboxylic acid compound of formula R1(COOH)m, a compound of formula R2AH and phosphorus pentasulfide, to form a dithiocarboxylic ester of structure I, 
where R1 represents a m-valent radical selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; R2 represents alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, and substituted alkylaryl; A represents S or O; and m is an integer from 1-6. This process is illustrated in Scheme A. In the scheme, one equivalent of a carboxylic acid compound reacts with one equivalent of an alcohol or thiol in the presence of one equivalent of phosphorus pentasulfide. Preferred dithiocarboxylic esters that may be prepared by the process are benzyl dithiobenzoate, benzyl-4-methoxydithiobenzoate, benzyl-4-fluorodithiobenzoate, benzyl-4-nitrodithiobenzoate, benzyl-4-cyanodithiobenzoate, benzyl-4-trifluoromethyldithiobenzoate, diphenyldithiobenzoate, propyl dithiobenzoate, benzyl dithiopropionate, and benzyl-4-chlorodithiobenzoate.
Phosphorus pentasulfide is known as a thiating agent for amides, ketones, aldehydes, esters, and thioesters. Typically, a 1:1:1 proportion of acid to alcohol/thiol to phosphorus pentasulfide is used. In some cases, it may be necessary to use an excess of the reagent to convert the esters to dithioesters. It will be noted that where substitutents of the substituted alkyl, aryl, alkylaryl or heteroaryl groups are amides, ketones, aldehydes, or esters, these groups may or may not be converted by the thiating agent to the corresponding S-containing compound. If an undesired conversion is expected to occur, it may be avoided by protecting the groups with a suitable protecting agent.
In another embodiment, a process according to the present invention comprises reacting a compound of formula R3(COAH)m, and a compound having structure II 
in the presence of a clay catalyst; and treating products of the reaction with a thiating agent to produce a dithiocarboxylic ester of structure III, a compound of structure IV, or a combination of compounds of structure III and structure IV. 
R3 may be alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; R4 is a n-valent radical selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; R5 is H or lower alkyl; A is S or O; and m and n are independently integers from 1-6, with the proviso that when m greater than 1, n=1 and when n greater than 1, m=1. Preferred dithiocarboxylic esters 1-10 that may be prepared by the process are shown in Table 1.
Thiating agents include phosphorus pentasulfide or Lawesson""s reagent, 2,4-bis-(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide. Preferably, the thiating agent is Lawesson""s reagent. 
As noted above, substituent groups, including amides, ketones, aldehydes, or esters, may or may not be converted by the thiating agent to the corresponding S-containing compound. For example, in a reaction between thiobenzoic acid and methylmethacrylate (MMA) according to Scheme B, the thioester group was converted to a dithioester, while the ester derived from MMA remained unconverted. If desired, the convertible group may be masked with a protecting group.
Suitable compounds of structure II include vinyl compounds, olefins, acrylates and methacrylates and styrene and styrene derivatives. Preferred compounds of this type are vinyl acetate, acrylate and methacrylate esters, styrene, xcex1-methylstyrene and p-methylstyrene. Divalent compounds, such as divinylbenzene, may also be used.
Suitable solvents for the reactions of Schemes A and B typically include ethers, aromatics, tertiary amines and chlorinated solvents pyridine, DMF, dioxane, acetonitrile, and THF. Toluene and benzene are preferred solvents. As phosphorus pentasulfide reacts with DMSO, primary and secondary amines, alcohols and neutral or acidic water, these solvents are generally avoided.
The reactions in Scheme A and B proceed under a wide range of temperature conditions, and preferably, from about 0xc2x0 C. to about 150xc2x0 C. More preferably, the temperature ranges from about 80xc2x0 C. to about 110xc2x0 C.